Anti-N-methyl-D-aspartate receptor encephalitis after coronavirus disease 2019: A case report and literature review

Rationale: Coronavirus disease 2019 (COVID-19) has become a global pandemic and COVID-19-associated anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may occur through an immune-mediated pathomechanism. Patient concerns: A 21-year-old woman with a history of COVID-19 presented to our hospital with memory decline and psychiatric symptoms. Diagnosis: The patient was diagnosed with anti-NMDAR encephalitis. Intervention: Intravenous methylprednisolone (1 g/day over 5 days) followed by immunoglobulin (0.4 g/kg/day over 5 days) were administered. The patient underwent laparoscopic salpingo-oophorectomy to remove an ovarian teratoma. Outcomes: The patient was discharged with sequelae of short-term memory impairment, without other neuropsychiatric symptoms. Lessons: Cases of previously reported anti-NMDAR encephalitis with COVID-19 were reviewed and compared with the present case. Clinicians should be aware of the occurrence of anti-NMDAR encephalitis in patients who present with neuropsychiatric complaints during or after exposure to COVID-19. Further studies are required to determine the causal relationship between the 2 diseases and predict the prognosis of anti-NMDAR encephalitis after COVID-19 exposure.


Introduction
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common form of autoimmune encephalitis, occurring more frequently in young women. It is also associated with tumors, especially ovarian teratomas. [1] About 80% of patients with anti-NMDAR encephalitis benefit from adaptive immunotherapy with or without removal of teratomas, and early tumor removal is associated with good prognosis. [1][2][3][4] Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in 2019, and various neurological diseases associated with it have been continuously reported. SARS-CoV-2 can invade the central nervous system through systemic circulation via angiotensin-converting enzyme 2 receptors and the cribriform plate. [5] Until now, only a few cases of anti-NMDAR encephalitis associated with COVID-19 have been reported. [6,7] Structural similarities between NMDAR and a subunit of SARS-CoV-2 may trigger anti-NMDAR encephalitis after COVID-19. [6] We report a case of a patient with anti-NMDAR encephalitis triggered by COVID-19. To the best of our knowledge, this is the first such case reported in East Asia.

Case report
A 21-year-old woman visited the emergency department with a complaint of short-term memory loss and abnormal behavior for past 1 week. She repeated the same words and presented an incoherent speech. She had no known underlying diseases and received the third dose of BNT162b2 vaccination against SARS-CoV-2 4 months prior to the visit. A polymerase chain reaction test performed on the nasopharyngeal swab collected from her approximately 10 days prior to admission was positive for COVID-19. Her abnormal behavior was noticed 3 days after SARS-CoV-2 infection was detected.
Laboratory tests revealed no abnormalities. Cerebrospinal fluid (CSF) analysis revealed a high opening pressure of 252 mm H 2 O, white blood cell count of 500/mm 3 (90% lymphocytes), red blood cell count of 85,700/mm 3 , protein level of 402.4 mg/ dL, glucose level of 57.8 mg/dL (serum glucose level of 104 mg/ dL), adenosine deaminase level of 5.9 IU/L, and corrected white blood cell count of 642.92/mm 3 . Brain fluid-attenuated inversion recovery images showed contrast-enhanced lesions in the cerebellum and hippocampus ( Fig. 1A-C). Electroencephalography exhibited diffuse beta wave activity with rare sharp waves in both the temporal lobes. Chest and abdomen-pelvic computed tomography revealed a mass of 5 cm in size in the right ovary, suspected to be a teratoma (Fig. 1D). Subsequently, her serum and CSF specimens were found to be positive for anti-NMDAR antibodies. The CSF oligoclonal band was negative; moreover, the serum was negative for paraneoplastic autoantibodies such as anti-Hu, Ri, Yo, amphiphysin, CV2, PNMA2 (Ma2/Ta), Recoverin, SOX1, and Titin.
Intravenous acyclovir (10 mg/kg per 8 hours for 8 days) and corticosteroids (methylprednisolone 1 g/day for 5 days) were initiated. Laparoscopic right salpingo-oophorectomy was performed. The psychosis, anxiety, and memory loss persisted even after treatment with corticosteroids. Therefore, intravenous immunoglobulin (0.4 g/kg/day over 5 days) was administered. She was discharged with improvement in psychosis. However, recovery of her memory impairment was incomplete, which would require continuous monitoring.

Discussion
Anti-NMDAR encephalitis occurs when antibodies against NMDAR are produced, and is triggered by herpes simplex type 1 encephalitis and tumors, including ovarian teratomas. [1] However, infection with diverse viruses including the Japanese encephalitis virus could also elicit anti-NMDAR encephalitis. [1,8] Furthermore, H1N1, polio, tetanus, diphtheria, and pertussis vaccination is also related to the manifestation of anti-NMDAR encephalitis. [8] Recently with the occurrence of the COVID-19 pandemic, some research regarding the relationship between COVID-19 and anti-NMDAR encephalitis has emerged. The subunits of NMDAR and non-structural proteins 8 and 9 in SARS-CoV-2 are structurally similar, and this mimicry may affect the cross-reactivity between them. [6] Furthermore, COVID-19 increases the release of inflammatory markers from the alveolar epithelium and macrophages. This leads to increased vascular permeability, and disruption of the blood-brain barrier. [9] Blood-brain barrier breakdown raises the risk of NMDAR antibodies invading the central nervous system. [6,10] Among more than 50 micro-ribonucleic acid biomarkers of COVID-19, 7 are known to be related to anti-NMDAR  Panariello et al 2020 [12] 23/M/Drug abuse 3 days prior and admission day: Psychomotor agitation, anxiety, thought disorganization, persecutory delusions, and auditory hallucinations  3 Monti et al 2020 [13] 50/M/Mild hypertension  5 Allahyari et al 2021 [15] 18/F/none encephalitis. [4] These common biomarkers are miR-107, miR-29b, let-7a, let-7f, miR-26b, miR-21, and miR-155; they do not contain the main biomarker for anti-NMDAR encephalitis (let-7b), yielding a ratio of <0.2. This may explain the low risk of anti-NMDAR encephalitis occurrence after COVID-19 infection. However, theses common micro-ribonucleic acid biomarkers may explain the causal relationship between COVID-19 and anti-NMDAR encephalitis. COVID-19 might trigger anti-NMDAR encephalitis using these common biomarkers, but the risk of occurrence may be low. [4] We reviewed published case reports of anti-NMDAR encephalitis related to COVID-19 in adults (aged ≥18 years or more) and found a total of 5 adult patients with anti-NMDAR encephalitis associated with COVID-19 (Table 1). [11][12][13][14][15] All these patients had psychiatric or behavioral symptoms and received immunotherapies such as steroids and intravenous immunoglobulin. However, unlike the previous 5 cases, our case had some distinct features.
In the current study, COVID-19 confirmation preceded the appearance of anti-NMDAR encephalitis symptoms. In previous cases, patients were confirmed to be positive for COVID-19 after their anti-NMDAR encephalitis related symptoms had appeared. The neurological manifestations of COVID-19 are similar to those of the anti-NMDAR encephalitis. Approximately 36.4% of patients with COVID-19 showed neurologic symptoms [16] making it difficult to distinguish whether the first neuropsychiatric symptoms are due to COVID-19 or anti-NMDAR encephalitis.
To the best of our knowledge, this is the first reported case of anti-NMDAR encephalitis suspected to be triggered by COVID-19, in East Asia. One recent study reviewed cases of autoimmune encephalitis in COVID-19 and suggested that their prognosis was relatively good. [7] Our case had relatively good prognosis except for memory impairment, and the other 5 cases had improvement of symptoms with some minor sequelae. This is similar to the outcome of the patient in our current study; however, the cognitive decline in the current patient remained significant. Additional studies with more cases are required to evaluate the prognosis of anti-NMDAR encephalitis after COVID-19.
There are some ambiguities related to the case. It is unclear whether the patient's neuropsychiatric symptoms were due to COVID-19 or anti-NMDAR encephalitis. In addition, it cannot be conclusively assumed that the patient's ovarian teratoma in our case had existed ever since the COVID-19 exposure. However, it can be concluded that when a patient with COVID-19 exhibits neuropsychiatric symptoms, anti-NMDAR encephalitis should be considered as a comorbidity.
Moreover, in the present case, we did not evaluate the CSF for Interleukin-6 (IL-6) or SARS-CoV-2. In COVID-19, a cytokine storm occurs and IL-6 increases during the inflammatory phase of COVID-19. In particular, elevated IL-6 levels in the CSF lead to increased production of autoantibodies in anti-NMDAR encephalitis. [13,17] Hence, CSF needs to be tested for IL-6 to clarify whether COVID-19 and anti-NMDAR encephalitis occurred during a similar duration of time by coincidence or they had a causal relationship.
To date, only a few cases of anti-NMDAR encephalitis triggered by COVID-19 have been reported. We report a case of anti-NMDAR encephalitis occurring after COVID-19 exposure in South Korea and compare the results with those of previous studies. COVID-19 may act as a trigger for the occurrence of anti-NMDAR encephalitis.
If a patient shows neuropsychiatric symptoms after COVID-19, suspecting an association with anti-NMDAR encephalitis is essential and the symptoms should not be regarded as an exclusive manifestation of COVID-19. With the accumulation of cases and data related to COVID-19 and anti-NMDAR encephalitis, we can anticipate to determine the epidemiology, establish an algorithm for effective treatments, and predict the prognosis of anti-NMDAR encephalitis following COVID-19 exposure.